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For Peer Review Journal: Brain Brain Brain ca techolamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency For Peer Review Journal: Brain Manuscript ID: BRAIN-2015-00246.R2 Manuscript Type: Original Article Date Submitted by the Author: n/a Complete List of Authors: Korner, Germaine; University of Zurich, Noain, Daniela; University of Zurich, Ying, Ming; University of Bergen, Hole, Magnus; University of Bergen, Flydal, Marte; University of Bergen, Scherer, Tanja; University of Zurich, Allegri, Gabriella; University of Zurich, Rassi, Anahita; University of Zurich, Fingerhut, Ralph; University of Zurich, Becu-Villalobos, Damasia; Institute of Biology and Experimental Medicine, Pillai, Samyuktha; University of Zurich, Wuuest, Stephan; University of Zurich, Konrad, Daniel; University of Zurich, Lauber-Biason, Anna; University of Fribourg, Baumann, Christian; University Hospital Zurich, Neurology Department Bindoff, Laurence; Haukeland University Hospital, Department of Neurology; University of Bergen, Department of Clinical Medicine Martinez, A; University of Bergen, Department of Biomedicine Thony, Beat; University of Zurich, Department of Pediatrics Subject category: Movement disorders Genetics: neuropathy < GENETICS, Metabolic disease < GENETICS, To search keyword list, use Dystonia < MOVEMENT DISORDERS, Movement disorders: other < whole or part words followed MOVEMENT DISORDERS, Cerebrospinal fluid < by an *: SYSTEMS/DEVELOPMENT/PHYSIOLOGY ScholarOne, 375 Greenbrier Drive, Charlottesville, VA, 22901 Support (434) 964 4100 Page 31 of 95 Brain Brain - Original Article Revision 2 final, June 17, 2015 Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency Germaine Korner,1,2,3,¶ Daniela Noain,4.¶ Ming Ying,5 Magnus Hole,5 Marte I. Flydal,5 Tanja Scherer,1,3 Gabriella Allegri,1,3 Anahita Rassi,6 Ralph Fingerhut,7,3 Damasia Becu-Villalobos,8 Samyuktha Pillai,9 Stephan Wueest,3,10 Daniel Konrad,3,10 Anna Lauber-Biason,11 Christian R. Baumann,2,4 Laurence A. Bindoff,12,13 Aurora Martinez 5,* and Beat Thöny 1,2,3,* (1) Division of Metabolism, Department of Pediatrics, University of Zürich, Zürich, Switzerland (2) Affiliated with theFor Neuroscience Peer Center Zurich Review (ZNZ), Zürich, Switzerland (3) Affiliated with the Children’s Research Centre (CRC), Zürich, Switzerland (4) Department of Neurology, University Hospital of Zurich, Zürich, Switzerland (5) Department of Biomedicine, University of Bergen, Bergen, Norway (6) Division of Clinical Chemistry and Biochemistry, Department of Pediatrics, University of Zürich, Zürich, Switzerland (7) Swiss Newborn Screening Laboratory, University Children’s Hospital, Zurich, Switzerland (8) Institute of Biology and Experimental Medicine, Buenos Aires, Argentina (9) Institute of Physiology, University of Zurich, Zürich, Switzerland (10) Division of Endocrinology, Department of Pediatrics, University of Zurich, Switzerland (11) Department of Medicine, University of Fribourg, Fribourg, Switzerland (12) Department of Clinical Medicine (K1), University of Bergen, Norway (13) Department of Neurology, Haukeland University Hospital, Bergen, Norway *Shared correspondence: Dr. Aurora Martinez , Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway, Tel: +47 55586427, [email protected] Dr. Beat Thöny , Division of Metabolism, Department of Pediatrics, University of Zurich, Steinwiesstrasse 75, CH-8032 Zürich, Switzerland, Tel +41 44 2667622; [email protected] ¶These authors contributed equally to this work Running title Molecular mechanism for severe TH deficiency Key words : infantile parkinsonism, dopamine deficiency, catecholamine deficiency, misfolding, mislocalization ScholarOne, 375 Greenbrier Drive, Charlottesville, VA, 22901 Support (434) 964 4100 1 Brain Page 32 of 95 Brain - Original Article Revision 2 final, June 17, 2015 Abbreviations: BH 4, (6 R)-L-erythro -5,6,7,8-tetrahydrobiopterin; DA, dopamine; DRD, Dopa-responsive dystonia; 5-HIAA, 5-hydroxyindolacetic acid; 5-HTP, 5-hydroxytryptophan; HVA, homovanillic acid; IGF-1, insulin-like growth factor 1; L-Dopa, L- dihydroxyphenylalanine; L-Tyr, L-tyrosine; MHPG, 3-methoxy-4-hydroxyphenylethylene glycol; TH, tyrosine hydroxylase; THD, tyrosine hydroxylase deficiency; tT4, total thyroid hormone thyroxine. For Peer Review ScholarOne, 375 Greenbrier Drive, Charlottesville, VA, 22901 Support (434) 964 4100 2 Page 33 of 95 Brain Brain - Original Article Revision 2 final, June 17, 2015 Abstract Tyrosine hydroxylase catalyzes the hydroxylation of L-tyrosine to L-Dopa, the rate-limiting step in the synthesis of catecholamines. Mutations in the TH gene encoding tyrosine hydroxylase are associated with the autosomal recessive disorder tyrosine hydroxylase deficiency, which manifests phenotypes varying from infantile parkinsonism and Dopa- responsive dystonia, also termed type A, to complex encephalopathy with perinatal onset, termed type B. We generated homozygous Th-knock-in mice with the mutation Th -p.R203H, equivalent to the most recurrent human mutation associated with type B tyrosine hydroxylase deficiency (TH -p.R233H), often unresponsive to L-Dopa treatment. The Th -knock-in mice showed normal survival and food intake, but hypotension, hypokinesia, reduced motor coordination, wide-basedFor gate andPeer catalepsy. ThisReview phenotype was associated to a gradual loss of central catecholamines and the serious manifestations of motor impairment presented diurnal fluctuation but did not improve with standard L-Dopa treatment. The mutant tyrosine hydroxylase enzyme was unstable and exhibited deficient stabilization by catecholamines, leading to decline of brain tyrosine hydroxylase-immunoreactivity in the Th knock-in mice. In fact the substantia nigra presented an almost normal level of mutant tyrosine hydroxylase protein but distinct absence of the enzyme was observed in the striatum, indicating a mutation-associated mislocalization of tyrosine hydroxylase in the nigrostriatal pathway. This hypomorphic mouse model thus provides understanding on pathomechanisms in type B tyrosine hydroxylase deficiency and a platform for the evaluation of novel therapeutics for movement disorders with loss of dopaminergic input to the striatum. ScholarOne, 375 Greenbrier Drive, Charlottesville, VA, 22901 Support (434) 964 4100 3 Brain Page 34 of 95 Brain - Original Article Revision 2 final, June 17, 2015 Introduction Tyrosine hydroxylase (TH; EC 1.14.16.2) is a homo-tetrameric enzyme that catalyzes the conversion of L-tyrosine (L-Tyr) to L-dihydroxyphenylalanine (L-Dopa) by using molecular oxygen as additional substrate and the cofactor (6 R)-L-erythro -5,6,7,8-tetrahydrobiopterin (BH 4) (Nagatsu et al. , 1964, Roberts and Fitzpatrick, 2013). This hydroxylation is the rate limiting step in the synthesis of the catecholamine neurotransmitters dopamine (DA), norepinephrine and epinephrine (Nagatsu et al. , 1964). DA is distinctively involved in motor control, but also in cognition, memory and reward, and, as a precursor of norepinephrine and epinephrine, indirectly regulates attention and helps to maintain normal blood pressure and blood sugar (Eisenhofer et al. , 2004). In the central nervous system (CNS), TH is mainly expressed in dopaminergicFor neurons Peer of the substantia Review nigra that projects mostly to the striatum and has a central role in motor control, and in the ventral tegmental area (VTA) that mainly projects to the nucleus accumbens and the prefrontal cortex and regulates motivation and reward. TH is also expressed in noradrenergic neurons of the locus coeruleus and lateral tegmental system (Zigmond et al. , 1989, Bjorklund and Dunnett, 2007). Outside the CNS, TH expression is found in the adrenal medulla , the sympathetic neurons, and in non-neuronal (renal, intestine, pancreatic and lymphoid) tissues. The single human TH gene undergoes alternative mRNA splicing generating four main isoforms (hTH1-hTH4), with variations in the length of the N-terminal, where hTH4 corresponds to the longest, full-length isoform and hTH1 to the shortest and most abundant one, equivalent to rodent TH (Nagatsu, 1995). TH activity is tightly controlled by regulatory mechanisms at the transcriptional, translational and posttranslational levels (Kumer and Vrana, 1996, Tank et al. , 2008). The latter includes phosphorylation at several Ser/Thr residues at the N-terminal tail (Daubner et al. , 2011). Notably, phosphorylation at Ser40 by cAMP dependent protein kinase A activates TH by releasing the feedback inhibition of catecholamines and decreasing the Km for the cofactor BH 4 (Nagatsu et al. , 1964). Binding of the catecholamine end-products inactivates and stabilizes TH both in vitro (Okuno and Fujisawa, 1991, Martinez et al. , 1996) and in vivo (Sumi-Ichinose et al. , 2001). Another short-term regulatory mechanism of TH of important biological significance is substrate inhibition, that allows steady synthesis of DA despite fluctuations in blood L-tyrosine (Reed et al. , 2010). Mutations in the TH gene (OMIM *191290) cause TH deficiency (THD; OMIM #605407), which is a rare disorder that comprises a broad phenotypic variation including infantile parkinsonism and Dopa-responsive dystonia (DRD). THD manifestations range from a mild progressive limb dystonia, postural tremor and hypokinetic rigid syndrome that is responsive to Dopa (termed type A) to a progressive and complex neonatal or early-infancy onset encephalopathy with Dopa-unresponsive
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